A prospective study undertaken by Bulbrook et al. on over 5000 women concluded that individuals who excrete low urinary levels of androsterone and etiocholanolone are predisposed to develop breast cancer. Low urinary levels of the above 2 steroids reflect low plasma concentrations of dehydroepiandrosterone (DHEA), and it has been found by Bulbrook and others that breast cancer patients do indeed have subnormal plasma concentrations of DHEA. We have found previously that DHEA protects cultured rodent cells against DMBA- and aflatoxin-induced cytotoxicity and transformation and inhibits metabolism of 3H-DMBA to water soluble products. DHEA has been found by others to be a potent inhibitor of mammalian glucose-6-phosphate dehydrogenase, the enzyme responsible for generating the bulk of extramitochondrial NADPH. Since NADPH is a necessary cofactor for the mixed-function oxidases, we have postulated that this steroid may inhibit carcinogen activation by reducing NADPH levels. Other have recently found that long-term treatment of mice with DHEA reduces their rate of weight gain without affecting their rate of food consumption, presumably by inhibiting lipogenesis. It is well documented that inhibition of weight gain by food restriction reduces the rate of spontaneous tumor formation and delays aging in rodents. We have obtained data that long-term DHEA treatment of C3H mice produces a very significant reduction in their rate of weight gain without affecting the rate of food consumption and have preliminary evidence that the hormone treated mice may be aging more slowly than the controls. We plan to extend these observations to determine if long-term DHEA treatment of male and female C3H mice will reduce the incidence of spontaneous hepatoma and breast cancer and prolong life span.